Solid dispersions of a erb2 (her2) inhibitor

ABSTRACT

A solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and processes for preparing the solid dispersion are provided herein. Also, a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and uses thereof are provided herein.

RELATED APPLICATIONS

This application a Continuation of U.S. patent application Ser. No.16/353,951, filed Mar. 14, 2019, which is a Continuation of U.S. patentapplication Ser. No. 15/275,163, filed Sep. 23, 2016, which is aContinuation of U.S. patent application Ser. No. 14/351,840, filed Apr.14, 2014, now U.S. Pat. No. 9,457,093, which is a 35 U.S.C § 371application of International Patent Application No. PCT/US2012/060044,filed Oct. 12, 2012, which claims the benefit of U.S. ProvisionalApplication No. 61/606,207, filed Mar. 2, 2012 and which also claims thebenefit of U.S Provisional Application No. 61/547,620, filed Oct. 14,2011. The entire content of the applications referenced above are herebyincorporated by reference herein.

FIELD OF THE INVENTION

A solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis provided herein. Also, a pharmaceutical composition comprising asolid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis provided herein.

DESCRIPTION OF THE STATE OF THE ART

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(also called “ARRY-380”), which has the structure:

is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257, whichis incorporated by reference in its entirety.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminehas been tested in human clinical trials for hyperproliferativediseases, particularly cancer (see Koch, Kevin. “ARRY-380: A Selective,Oral HER2 Inhibitor for the Treatment of Solid Tumors.” AmericanAssociation of Cancer Research 102^(nd) Annual Meeting, Apr. 3, 2011;which may also be found at:http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf).

A powder-in-capsule (“PIC”) composition ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminewas prepared and administered to patients with cancer, and the overallinter-patient variability for area under the plasma concentration-timecurve (“AUC”) and maximum concentration (“Cmax”) was moderate to high.

There remains a need to prepare a pharmaceutical composition containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminethat minimizes inter-patient variability of pharmacokinetics.

SUMMARY OF THE INVENTION

A solid dispersion comprisingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described herein.

A pharmaceutical composition comprisingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described herein.

A pharmaceutical composition comprising a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described herein.

A pharmaceutical composition comprising a solid dispersion of spraydried N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described herein.

Processes for preparing the solid dispersion and pharmaceuticalcomposition and methods of using the pharmaceutical composition are alsodescribed herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a comparison of XRPD scans of amorphous 30% soliddispersions and crystallineN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine,with a close up of the amorphous solid dispersions.

FIG. 2 shows a dissolution profile of a 30% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 3 shows a dissolution profile of a 30% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 4 shows a dissolution profile of a 30% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 5 shows a dissolution profile of a 30% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 6 shows a dissolution profile of a 30% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 7 shows a comparison of XRPD scans of amorphous 60% soliddispersions and crystallineN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine,with a close up of the amorphous solid dispersions.

FIG. 8 shows a dissolution profile of a 60% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 9 shows a dissolution profile of a 60% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 10 shows a dissolution profile of a 60% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 11 shows a dissolution profile of a 60% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 12 shows a dissolution profile of a 60% solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 13 shows a dissolution comparison of a solid dispersion tablet anda crystalline PIC composition.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments, examples ofwhich are illustrated herein. While enumerated embodiments will bedescribed, it will be understood that they are not intended to limit theinvention to those embodiments. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims. One skilled in the art will recognize manymethods and materials similar or equivalent to those described herein,which could be used in the practice of the present invention. Thepresent invention is in no way limited to the methods and materialsdescribed. In the event that one or more of the incorporated literatureand similar materials differs from or contradicts this application,including but not limited to defined terms, term usage, describedtechniques, or the like, this application controls.

Definitions

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable thatis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable that is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable that is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables that areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue for variables that are inherently continuous.

The term “amorphous” means a solid in a solid state that is anon-crystalline state. Amorphous solids generally possess crystal-likeshort range molecular arrangement, but no long range order of molecularpacking as found in crystalline solids. The solid state form of a solidmay be determined by polarized light microscopy, x-ray powderdiffraction (“XRPD”), differential scanning calorimetry (“DSC”), orother standard techniques known to those of skill in the art.

The phrase “amorphous solid dispersion” means a solid comprising a drugsubstance and a dispersion polymer. The amorphous solid dispersiondiscussed herein comprises amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a dispersion polymer, wherein the amorphous solid dispersioncontainsN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein a substantially amorphous solid state form. In certain embodiments,the substantially amorphous solid state form means that theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminecomponent in the amorphous solid dispersion is at least 80% amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.In certain embodiments, the substantially amorphous solid state formmeans that theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminecomponent in the amorphous solid dispersion is at least 85% amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.In certain embodiments, the substantially amorphous solid state formmeans that theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminecomponent in the amorphous solid dispersion is at least 90% amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.In certain embodiments, the substantially amorphous solid state formmeans that theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminecomponent in the amorphous solid dispersion is at least 95% amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byabnormal or unregulated cell growth. A “tumor” comprises one or morecancerous cells. Examples of cancer include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include squamouscell cancer (e.g., epithelial squamous cell cancer), lung cancerincluding small cell lung cancer, non-small cell lung cancer (“NSCLC”),adenocarcinoma of the lung and squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma,breast cancer, colon cancer, rectal cancer, colorectal cancer, brain,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, skin cancer, includingmelanoma, as well as head and neck cancer.

The phrase “dispersion polymer” means a polymer that allows forN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineto be dispersed throughout such that a solid dispersion may form. Thedispersion polymer is preferably neutral or basic. The dispersionpolymer may contain a mixture of two or more polymers. Examples ofdispersion polymers include, but are not limited to, vinyl polymers andcopolymers, vinylpyrrolidine vinylacetate copolymer (“PVP-VA”),polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers,polyvinyl pyrrolidine (“PVP”), acrylate and methacrylate copolymers,methylacrylic acid methyl methacrylate copolymer (such as Eudragit®),polyethylene polyvinyl alcohol copolymers,polyoxyethylene-polyoxypropylene block copolymers (also referred to aspoloxamers), graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate (such as Soluplus®), cellulosicpolymers, such as hydroxypropyl methyl cellulose acetate (“HPMCA”),hydroxypropyl methyl cellulose (“HPMC”), hydroxypropyl cellulose(“HPC”), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate (“HPMCAS”),hydroxypropyl methyl cellulose phthalate (“HPMCP”), carboxymethylethylcellulose (“CMEC”), cellulose acetate phthalate (“CAP”), celluloseacetate succinate (“CAS”), hydroxypropyl methyl cellulose acetatephthalate (“HPMCAP”), cellulose acetate trimellitate (“CAT”),hydroxypropyl methyl cellulose acetate trimellitate (“HPMCAT”), andcarboxymethylcellulose acetate butyrate (“CMCAB”), and the like.

The term “mammal” means a warm-blooded animal that has or is at risk ofdeveloping a disease described herein and includes, but is not limitedto, guinea pigs, dogs, cats, rats, mice, hamsters, and primates,including humans.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a composition, and/or the mammal beingtreated therewith.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compounddescribed herein.

The phrase “solid dispersion” means a system in a solid state comprisingat least two components, wherein one component is dispersed throughoutthe other component. The solid dispersion discussed herein comprises onecomponent ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminedispersed throughout another component, particularly a dispersionpolymer.

The phrase “spray drying” means processes involved in breaking up liquidmixtures into small droplets (atomization) and rapidly removing solventfrom the mixture in a spray drying apparatus where there is a strongdriving force for evaporation of solvent from the droplets. The phrasespray drying is used conventionally and broadly. Spray drying processesand spray drying equipment are described generally in Perry, Robert H.,and Don W. Green (eds.). Perry's Chemical Engineers' Handbook. New York:McGraw-Hill, 2007 (8^(th) edition).

The phrases “therapeutically effective amount” or “effective amount”mean an amount of a compound described herein that, when administered toa mammal in need of such treatment, sufficient to (i) treat or preventthe particular disease, condition, or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) prevent or delay the onset of one ormore symptoms of the particular disease, condition, or disorderdescribed herein. The amount of a compound that will correspond to suchan amount will vary depending upon factors such as the particularcompound, disease condition and its severity, the identity (e.g.,weight) of the mammal in need of treatment, but can nevertheless beroutinely determined by one skilled in the art.

The terms “treat” or “treatment” refer to therapeutic, prophylactic,palliative or preventative measures. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder, as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

Solid Dispersions and Pharmaceutical Compositions

Provided herein is a solid dispersion comprisingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4, 5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

The solid dispersions are generally prepared by dissolving the drugsubstance and the dispersion polymer in a suitable solvent to form afeed solution, and then the feed solution may be spray dried to form thesolid dispersion (and remove the solvent). Spray drying is a knownprocess. Spray drying is generally performed by dissolvingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymerin a suitable solvent to prepare a feed solution. The feed solution maybe pumped through an atomizer into a drying chamber. The feed solutioncan be atomized by conventional means known in the art, such as atwo-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and atwo-fluid non-sonicating nozzle. Then, the solvent is removed in thedrying chamber to form the solid dispersion. A typical drying chamberuses hot gases, such as forced air, nitrogen, nitrogen-enriched air, orargon to dry particles. The size of the drying chamber may be adjustedto achieve particle properties or throughput.

Although the solid dispersion are preferably prepared by conventionalspray drying techniques, other techniques known in the art may be used,such as melt extrusion, freeze drying, rotary evaporation, drum dryingor other solvent removal processes.

In one embodiment, a process of preparing a solid dispersion isprovided, comprising:

(a) dissolvingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a dispersion polymer in a suitable solvent; and

(b) evaporating the solvent to form the solid dispersion.

In a further embodiment, the evaporation of the solvent in step (b) isperformed by spray drying, melt extrusion, freeze drying, rotaryevaporation, drum drying or other solvent removal processes.

In certain embodiments, the dispersion polymer is selected from PVP-VA,methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS andHPMC and mixtures thereof. In certain embodiments, the dispersionpolymer is selected from PVP-VA, methylacrylic acid methyl methacrylatecopolymer, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, thedispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55,CAP, HPMCAS Grade M, HPMC and mixtures thereof. In certain embodiments,the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCPH-55, CAP, HPMCAS Grade M and HPMC.

In certain embodiments, the dispersion polymer is selected from PVP-VA,methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS,and mixtures thereof. In certain embodiments, the dispersion polymer isselected from PVP-VA, methylacrylic acid methyl methacrylate copolymer,HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer isselected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS GradeM, and mixtures thereof. In certain embodiments, the dispersion polymeris selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCASGrade M.

In certain embodiments, the dispersion polymer is selected from PVP-VA,methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC,and mixtures thereof. In certain embodiments, the dispersion polymer isselected from PVP-VA, methylacrylic acid methyl methacrylate copolymer,HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer isselected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC, andmixtures thereof. In certain embodiments, the dispersion polymer isselected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.

In certain embodiments, the dispersion polymer is selected from PVP-VA,methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, andmixtures thereof. In certain embodiments, the dispersion polymer isselected from PVP-VA, methylacrylic acid methyl methacrylate copolymer,HPMCP and CAP. In certain embodiments, the dispersion polymer isselected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and mixturesthereof. In certain embodiments, the dispersion polymer is selected fromPVP-VA, Eudragit® L100, HPMCP H-55 and CAP.

In certain embodiments, the dispersion polymer is PVP-VA.

In certain embodiments, the dispersion polymer is methylacrylic acidmethyl methacrylate copolymer. In certain embodiments, the dispersionpolymer is Eudragit®. In certain embodiments, the dispersion polymer isEudragit® L100.

In certain embodiments, the dispersion polymer is HPMCP. In certainembodiments, the dispersion polymer is HPMCP H-55.

In certain embodiments, the dispersion polymer is CAP.

In certain embodiments, the dispersion polymer is HPMCAS. In certainembodiments, the dispersion polymer is HPMCAS Grade M.

In certain embodiments, the dispersion polymer is preferably neutral orbasic. In certain embodiments, the dispersion polymer is selected fromPVP-VA and HPMC. In certain embodiments, the dispersion polymer is HPMC.

Suitable solvents are a solvent or mixture of solvents in which bothN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand the dispersion polymer have adequate solubility (solubility greaterthan 1 mg/mL). A mixture of solvents may be used if each component ofthe solid dispersion (i.e.,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand dispersion polymer) require different solvents to obtain the desiredsolubility. The solvent may be volatile with a boiling point of 150° C.or less. In addition, the solvent should have relatively low toxicityand be removed from the dispersion to a level that is acceptable to TheInternational Committee on Harmonization (“ICH”) guidelines. Removal ofsolvent to this level may require a subsequent processing step, such astray drying. Examples of suitable solvents include, but are not limitedto, alcohols, such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol,isopropanol (“IPA”) and butanol; ketones, such as acetone, methyl ethylketone (“MEK”) and methyl isobutyl ketone; esters, such as ethyl acetate(“EA”) and propyl acetate; and various other solvents, such astetrahydrofuran (“THF”), acetonitrile (“ACN”), methylene chloride,toluene and 1,1,1-trichloroethane. Lower volatility solvents, such asdimethyl acetate or dimethylsulfoxide (“DMSO”), may be used. Mixtures ofsolvents with water may also be used, so long as the polymer andN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineare sufficiently soluble to make the spray drying process practicable.Generally, due to the hydrophobic nature of low solubility drugs,non-aqueous solvents may be used, meaning the solvent comprises lessthan about 10 weight % water.

In certain embodiments, the suitable solvent is selected from MeOH andTHF, and mixtures thereof. In certain embodiments, the suitable solventis MeOH:THF solvent system of about 1:3. In certain embodiments, thesuitable solvent is a 1:3 MeOH:THF solvent system.

In certain embodiments, the suitable solvent is selected from MeOH, THFand water, and mixtures thereof. In certain embodiments, the suitablesolvent is selected from MeOH, THF and water. In certain embodiments,the suitable solvent is a THF:MeOH:water solvent system of about80:10:10. In certain embodiments, the suitable solvent is a 80:10:10THF:MeOH:water solvent system. In certain embodiments, the suitablesolvent is a THF:MeOH:water solvent system of about 82:8:10. In certainembodiments, the suitable solvent is a 82:8:10 THF:MeOH:water solventsystem. In certain embodiments, the suitable solvent is a THF:MeOH:watersolvent system of about 82.2:8.2:9.6. In certain embodiments, thesuitable solvent is a 82.2:8.2:9.6 THF:MeOH:water solvent system.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 0.1% to about 70% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 0.1% to 70% by weight relative tothe dispersion polymer.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 1% to about 60% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 1% to 60% by weight relative to thedispersion polymer.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 5% to about 60% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 5% to 60% by weight relative to thedispersion polymer.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 55% to about 65% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 55% to 65% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is about 60% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is 60% by weight relative to the dispersionpolymer.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 25% to about 35% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 25% to 35% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is about 30% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is 30% by weight relative to the dispersionpolymer.

In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from about 45% to about 55% by weightrelative to the dispersion polymer. In certain embodiments, the amountofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion ranges from 45% to 55% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is about 50% by weight relative to thedispersion polymer. In certain embodiments, the amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminein the solid dispersion is 50% by weight relative to the dispersionpolymer.

In certain embodiments, the solid dispersion is an amorphous soliddispersion.

Another embodiment provides a pharmaceutical composition comprising asolid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a dispersion polymer, and a carrier or excipient.

Suitable carriers and excipients are well known to those skilled in theart and are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

The pharmaceutical compositions may also include one or more additionalcomponents, such as buffers, dispersion agents, surfactants, wettingagents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug,i.e., a compound described herein or pharmaceutical composition thereof,or aid in the manufacturing of the pharmaceutical product, i.e.,medicament (see Ansel; Gennaro; and Rowe above). The components of thepharmaceutical composition should be pharmaceutically acceptable.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 1 to about 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 0.1 to about 20 weight % of a disintegrant;

(c) about 0.1 to about 25 weight % of an osmogen;

(d) about 0.1 to about 10 weight % of a glidant;

(e) about 0.1 to about 10 weight % of a lubricant; and

(f) about 0.1 to about 25 weight % of a binder/diluent.

In a further embodiment, the pharmaceutical composition comprises:

(a) 1 to 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 0.1 to 20 weight % of a disintegrant;

(c) 0.1 to 25 weight % of an osmogen;

(d) 0.1 to 10 weight % of a glidant;

(e) 0.1 to 10 weight % of a lubricant; and

(f) 0.1 to 25 weight % of a binder/diluent.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 25 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 5 to about 15 weight % of a disintegrant;

(c) about 15 to about 25 weight % of an osmogen;

(d) about 0.1 to about 3 weight % of a glidant;

(e) about 0.1 to about 3 weight % of a lubricant; and

(f) about 10 to about 25 weight % of a binder/diluent.

In a further embodiment, the pharmaceutical composition comprises:

(a) 25 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 5 to 15 weight % of a disintegrant;

(c) 15 to 25 weight % of an osmogen;

(d) 0.1 to 3 weight % of a glidant;

(e) 0.1 to 3 weight % of a lubricant; and

(f) 10 to 25 weight % of a binder/diluent.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 40 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 5 to about 15 weight % of a disintegrant;

(c) about 15 to about 25 weight % of an osmogen;

(d) about 0.1 to about 3 weight % of a glidant;

(e) about 0.1 to about 3 weight % of a lubricant; and

(f) about 10 to about 25 weight % of a binder/diluent.

In a further embodiment, the pharmaceutical composition comprises:

(a) 40 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 5 to 15 weight % of a disintegrant;

(c) 15 to 25 weight % of an osmogen;

(d) 0.1 to 3 weight % of a glidant;

(e) 0.1 to 3 weight % of a lubricant; and

(f) 10 to 25 weight % of a binder/diluent.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 1 to about 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 0.1 to about 20 weight % of a disintegrant;

(c) about 0.1 to about 25 weight % of an osmogen;

(d) about 0.1 to about 10 weight % of a glidant;

(e) about 0.1 to about 10 weight % of a lubricant; and

(f) about 0.1 to about 25 weight % of a filler.

In a further embodiment, the pharmaceutical composition comprises:

(a) 1 to 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 0.1 to 20 weight % of a disintegrant;

(c) 0.1 to 25 weight % of an osmogen;

(d) 0.1 to 10 weight % of a glidant;

(e) 0.1 to 10 weight % of a lubricant; and

(f) 0.1 to 25 weight % of a filler.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 25 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 1 to about 10 weight % of a disintegrant;

(c) about 15 to about 25 weight % of an osmogen;

(d) about 0.1 to about 3 weight % of a glidant;

(e) about 0.1 to about 3 weight % of a lubricant; and

(f) about 10 to about 25 weight % of a filler.

In a further embodiment, the pharmaceutical composition comprises:

(a) 25 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 1 to 10 weight % of a disintegrant;

(c) 15 to 25 weight % of an osmogen;

(d) 0.1 to 3 weight % of a glidant;

(e) 0.1 to 3 weight % of a lubricant; and

(f) 10 to 25 weight % of a filler.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 40 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 1 to about 10 weight % of a disintegrant;

(c) about 15 to about 25 weight % of an osmogen;

(d) about 0.1 to about 3 weight % of a glidant;

(e) about 0.1 to about 3 weight % of a lubricant; and

(f) about 10 to about 25 weight % of a filler.

In a further embodiment, the pharmaceutical composition comprises:

(a) 40 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 1 to 10 weight % of a disintegrant;

(c) 15 to 25 weight % of an osmogen;

(d) 0.1 to 3 weight % of a glidant;

(e) 0.1 to 3 weight % of a lubricant; and

(f) 10 to 25 weight % of a filler.

In certain embodiments, the osmogen is selected from NaCl and KCl, andmixtures thereof.

In certain embodiments, the lubricant is magnesium stearate.

In certain embodiments, the glidant is colloidal silicon dioxide.

In certain embodiments, the binder/diluent is microcrystallinecellulose. In certain embodiments, the binder/diluent acts as both abinder and a diluent.

In certain embodiments, the binder is microcrystalline cellulose.

In certain embodiments, the diluent is microcrystalline cellulose.

In certain embodiments, the filler is lactose.

In certain embodiments, the disintegrant is selected from crospovidoneand sodium bicarbonate (NaHCO₃), and mixtures thereof. In certainembodiments, the disintegrant is selected from crospovidone and sodiumbicarbonate. In certain embodiments, the disintegrant is sodiumbicarbonate. In certain embodiments, the disintegrant is crospovidone.

In certain embodiments, the composition contains sodium bicarbonate.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may slowly degrade, throughhydrolysis or other means, to a carbamate impurity:

Sodium bicarbonate helps to slow the degradation to the carbamateimpurity. Sodium bicarbonate also helps to provide consistent tabletdisintegration when the tablets are exposed to different humidities.

Certain embodiments provide a pharmaceutical composition comprising:

(a)N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) sodium bicarbonate.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 1 to about 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) about 0.1 to about 30 weight % sodium bicarbonate.

In a further embodiment, the pharmaceutical composition comprises:

(a) 1 to 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) 0.1 to 30 weight % sodium bicarbonate.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 1 to about 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 0.1 to about 30 weight % sodium bicarbonate; and

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

In a further embodiment, the pharmaceutical composition comprises:

(a) 1 to 70 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 0.1 to 30 weight % sodium bicarbonate; and

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 25 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) about 1 to about 15 weight % of sodium bicarbonate.

In a further embodiment, the pharmaceutical composition comprises:

(a) 25 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4, 5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and

(b) 1 to 15 weight % of sodium bicarbonate.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 25 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 1 to about 15 weight % of sodium bicarbonate; and

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

In a further embodiment, the pharmaceutical composition comprises:

(a) 25 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 1 to 15 weight % of sodium bicarbonate; and

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 40 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) about 1 to about 15 weight % of sodium bicarbonate.

In a further embodiment, the pharmaceutical composition comprises:

(a) 40 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;and

(b) 1 to 15 weight % of sodium bicarbonate.

Certain embodiments provide a pharmaceutical composition comprising:

(a) about 40 to about 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) about 1 to about 15 weight % of sodium bicarbonate;

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

In a further embodiment, the pharmaceutical composition comprises:

(a) 40 to 60 weight % of a solid dispersion ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(b) 1 to 15 weight % of sodium bicarbonate;

(c) the remaining weight is other pharmaceutically acceptable excipientsand carriers.

The pharmaceutical composition preferably contains a therapeuticallyeffective amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.However, in some embodiments, each individual dose contains a portion ofa therapeutically effective amount ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine,such that multiple doses of the composition may be required (forexample, two or more tablets are required for a therapeuticallyeffective amount). Thus, in this application when it states that thepharmaceutical composition contains a therapeutically effective amountit means that the composition may be one dose (for example, one tablet)or multiple doses (for example, two tablets). In certain embodiments,the pharmaceutical composition contains between 1 and 500 mg ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

In certain embodiments, the pharmaceutical composition contains between25 and 400 mg ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

In certain embodiments, the pharmaceutical composition contains between100 and 300 mg ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

The pharmaceutical compositions described herein may be administered byany convenient route appropriate to the condition to be treated.Suitable routes include oral, parenteral (including subcutaneous,intramuscular, intravenous, intraarterial, intradermal, intrathecal andepidural), transdermal, rectal, nasal, topical (including buccal andsublingual), ocular, vaginal, intraperitoneal, intrapulmonary andintranasal. If parenteral administration is desired, the compositionswill be sterile and in a solution or suspension form suitable forinjection or infusion.

The compounds may be administered in any convenient administrative form,e.g., tablets, powders, capsules, dispersions, suspensions, syrups,sprays, suppositories, gels, emulsions, patches, etc.

The pharmaceutical compositions described herein are typicallyadministered orally. The pharmaceutical compositions described hereinare typically administered as a tablet, caplet, hard or soft gelatincapsule, pill, granules or a suspension.

Methods of Treatment with Compounds of the Invention

Also provided are methods of treating or preventing disease or conditionby administering the pharmaceutical composition described herein. In oneembodiment, a human patient is treated with a pharmaceutical compositiondescribed herein in an amount to inhibit ErbB2 activity. In oneembodiment, a human patient is treated with a pharmaceutical compositiondescribed herein in an amount to detectably inhibit ErbB2 activity.

In another embodiment, a method of treating a hyperproliferative diseasein a mammal comprising administering the pharmaceutical compositiondescribed herein, to the mammal is provided.

In certain embodiments, the hyperproliferative disease is cancer.

In another embodiment, a method of treating or preventing cancer in amammal in need of such treatment, wherein the method comprisesadministering to said mammal a pharmaceutical composition describedherein. The cancer is selected from breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lungadenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma,seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma andbiliary passages, kidney carcinoma, myeloid disorders, lymphoiddisorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue,mouth, pharynx, small intestine, colon-rectum, large intestine, rectum,brain and central nervous system, Hodgkin's and leukemia. Anotherembodiment provides the use of a pharmaceutical composition describedherein, in the manufacture of a medicament for the treatment of cancer.

In another embodiment, the cancer is ErbB2 positive.

In another embodiment, the cancer is selected from breast, gastric,biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian,uterine and brain cancer.

In another embodiment, the cancer is selected from breast, gastric,biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian anduterine cancer.

In another embodiment, the cancer is selected from breast, gastric,colorectal, lung and ovarian cancer.

In another embodiment, the cancer is selected from breast, ovarian,gastric and uterine cancer.

In another embodiment, the cancer is selected from breast, gastric,colorectal, NSCLC and ovarian cancer.

In another embodiment, the cancer is selected from breast, lung,pancreatic, colorectal and head and neck cancers.

In another embodiment, the cancer is breast cancer.

In another embodiment, the cancer is gastric cancer.

In another embodiment, the cancer is biliary cancer.

In another embodiment, the cancer is colorectal cancer.

In another embodiment, the cancer is lung cancer.

In another embodiment, the cancer is NSCLC.

In another embodiment, the cancer is pancreatic cancer.

In another embodiment, the cancer is head and neck cancer.

In another embodiment, the cancer is ovarian cancer.

In another embodiment, the cancer is uterine cancer.

In another embodiment, the cancer is brain cancer.

In another embodiment, a method of treating or preventing a disease ordisorder modulated by ErbB2, comprising administering to a mammal inneed of such treatment an effective amount of a pharmaceuticalcomposition described herein. Examples of such diseases and disordersinclude, but are not limited to, cancer.

Another embodiment provides the use of a pharmaceutical compositiondescribed herein, in the manufacture of a medicament for the treatmentof cancer.

Another embodiment provides the solid dispersions described herein forthe treatment of disease. In a further embodiment, the disease is ahyperproliferative disease. In a further embodiment, thehyperproliferative disease is cancer.

Another embodiment provides the pharmaceutical compositions describedherein for the treatment of disease. In a further embodiment, thedisease is a hyperproliferative disease. In a further embodiment, thehyperproliferative disease is cancer.

EXAMPLES

For illustrative purposes, the following Examples are included. However,it is to be understood that these Examples do not limit the inventionand are only meant to suggest a method of practicing the invention.Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare the compounds describedherein, and alternative methods for preparing the compounds are deemedto be within the scope of this invention. For example, the synthesis ofthe compounds described herein may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing the compounds described herein.Persons skilled in the art will also recognize that the soliddispersions and compositions described may be readily adapted to prepareother dispersions and compositions, and alternative methods forpreparing the dispersions and compositions, as well as alternativecompositions are deemed to be within the scope of this invention.

Example 1 30% Solid Dispersion Using PVP-VA

A solid dispersion was prepared containing 30 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand PVP-VA using a Buchi B-290 mini spray drier. The solid dispersionwas spray dried from a MeOH:THF (1:3) solvent system, a 5% spraysolution concentration, an inlet temperature of 100° C. at a flow rateof 22 mL/minute, drying gas flow rate of 35 m³/hour, nozzle pressure of80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mm nozzle type.Secondary drying of the dispersion was done at 40° C. under vacuum forabout 16 hours. The spray drying yielded 19.6 g (87.7% yield) of thesolid dispersion. Physicochemical analysis results are in Table 1. TheXRPD scan is shown in FIG. 1. Residual solvent analysis showed that thedispersion had less than 0.5% THF and no detectable MeOH.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 2. The Cmax and AUCfor the total drug species (colloidal+free) was 63.46 μg/mL and 245.05μg/mL*hr, respectively. The Cmax and AUC for the free drug species was52.50 μg/mL and 204.12 μg/mL*hr, respectively.

Example 2 30% Solid Dispersion Using Eudragit

A solid dispersion was prepared containing 30 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand Eudragit L100 using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 100° C. at a flowrate of 22 mL/minute, drying gas flow rate of 35 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 18.6 g (82.7% yield)of the solid dispersion. Physicochemical analysis results are inTable 1. The XRPD scan is shown in FIG. 1. Residual solvent analysisshowed that the dispersion had about 4.5% THF and no detectable MeOH.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 3. The Cmax and AUCfor the total drug species (colloidal+free) was 22.70 μg/mL and 71.06μg/mL*hr, respectively. The Cmax and AUC for the free drug species was9.26 μg/mL and 35.49 μg/mL*hr, respectively.

Example 3 30% Solid Dispersion Using HPMCP

A solid dispersion was prepared containing 30 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand HPMCP H-55 using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 100° C. at a flowrate of 22 mL/minute, drying gas flow rate of 35 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 20.3 g (90.3% yield)of the solid dispersion. Physicochemical analysis results are inTable 1. The XRPD scan is shown in FIG. 1. Residual solvent analysisshowed that the dispersion had less than 0.5% THF and no detectableMeOH.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 4. The Cmax and AUCfor the total drug species (colloidal+free) was 25.00 μg/mL and 96.66μg/mL*hr, respectively. The Cmax and AUC for the free drug species was16.15 μg/mL and 56.81 μg/mL*hr, respectively.

Example 4 30% Solid Dispersion Using CAP

A solid dispersion was prepared containing 30 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand CAP using a Buchi B-290 mini spray drier. The solid dispersion wasspray dried from a MeOH:THF (1:3) solvent system, a 5% spray solutionconcentration, an inlet temperature of 100° C. at a flow rate of 22mL/minute, drying gas flow rate of 35 m³/hour, nozzle pressure of 80psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mm nozzle type.Secondary drying of the dispersion was done at 40° C. under vacuum forabout 16 hours. The spray drying yielded 20.0 g (90.4% yield) of thesolid dispersion. Physicochemical analysis results are in Table 1. TheXRPD scan is shown in FIG. 1. Residual solvent analysis showed that thedispersion had less than 0.5% THF and no detectable MeOH.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 5. The Cmax and AUCfor the total drug species (colloidal+free) was 11.62 μg/mL and 36.69μg/mL*hr, respectively. The Cmax and AUC for the free drug species was5.64 μg/mL and 20.58 μg/mL*hr, respectively.

Example 5 30% Solid Dispersion Using HPMCAS

A solid dispersion was prepared containing 30 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand HPMCAS Grade M using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 80° C. at a flowrate of 35 mL/minute, drying gas flow rate of 40 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 163.19 mg (48.3%yield) of the solid dispersion. Physicochemical analysis results are inTable 1. The XRPD scan is shown in FIG. 1. Residual solvent analysisshowed that the dispersion had less than 0.5% THF and no detectableMeOH.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 6. The Cmax and AUCfor the total drug species (colloidal+free) was 19.04 μg/mL and 68.09μg/mL*hr, respectively. The Cmax and AUC for the free drug species was13.50 μg/mL and 51.74 μg/mL*hr, respectively.

TABLE 1 TGA Hygroscopicity HPLC T_(g) wt loss % THF (% wt change ExamplePolymer API:Polymer (area %) (° C.) (%) (w/w) at 80% RH) REF 99.39 4.9<1% 1 PVP-VA 3:7 99.45 117 2.3 0.5 14.4 2 Eudragit 3:7 98.63 116 5.9 4.57.5 L100 3 HPMCP 3:7 97.30 149 1.7 0.3 7.5 H-55 4 CAP 3:7 95.45 179 1.90.5 7.8 5 HPMCAS 3:7 113 NA NA NA

Example 6 60% Solid Dispersion Using PVP-VA

A solid dispersion was prepared containing 60 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand PVP-VA using a Buchi B-290 mini spray drier. The solid dispersionwas spray dried from a MeOH:THF (1:3) solvent system, a 5% spraysolution concentration, an inlet temperature of 80° C. at a flow rate of35 mL/minute, drying gas flow rate of 40 m³/hour, nozzle pressure of 80psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mm nozzle type.Secondary drying of the dispersion was done at 40° C. under vacuum forabout 16 hours. The spray drying yielded 135.0 mg (88.2% yield) of thesolid dispersion. The XRPD scan is shown in FIG. 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 8. The Cmax and AUCfor the total drug species (colloidal+free) was 34.80 μg/mL and 133.76μg/mL*hr, respectively. The Cmax and AUC for the free drug species was21.88 μg/mL and 84.43 μg/mL*hr, respectively.

Example 7 60% Solid Dispersion Using Eudragit

A solid dispersion was prepared containing 60 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand Eudragit L100 using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 80° C. at a flowrate of 35 mL/minute, drying gas flow rate of 40 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 88.1 mg (52.4%yield) of the solid dispersion. The XRPD scan is shown in FIG. 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 9. The Cmax and AUCfor the total drug species (colloidal+free) was 26.82 μg/mL and 84.49μg/mL*hr, respectively. The Cmax and AUC for the free drug species was9.85 μg/mL and 34.89 μg/mL*hr, respectively.

Example 8 60% Solid Dispersion Using HPMCP

A solid dispersion was prepared containing 60 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand HPMCP H-55 using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 80° C. at a flowrate of 35 mL/minute, drying gas flow rate of 40 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 98.0 mg (58.0%yield) of the solid dispersion. The XRPD scan is shown in FIG. 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 10. The Cmax andAUC for the total drug species (colloidal+free) was 32.21 μg/mL and38.28 μg/mL*hr, respectively. The Cmax and AUC for the free drug specieswas 9.96 μg/mL and 38.28 μg/mL*hr, respectively.

Example 9 60% Solid Dispersion Using CAP

A solid dispersion was prepared containing 60 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand CAP using a Buchi B-290 mini spray drier. The solid dispersion wasspray dried from a MeOH:THF (1:3) solvent system, a 5% spray solutionconcentration, an inlet temperature of 80° C. at a flow rate of 35mL/minute, drying gas flow rate of 40 m³/hour, nozzle pressure of 80psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mm nozzle type.Secondary drying of the dispersion was done at 40° C. under vacuum forabout 16 hours. The spray drying yielded 74.9 mg (44.6% yield) of thesolid dispersion. The XRPD scan is shown in FIG. 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 11. The Cmax andAUC for the total drug species (colloidal+free) was 51.98 μg/mL and144.91 μg/mL*hr, respectively. The Cmax and AUC for the free drugspecies was 15.07 μg/mL and 59.69 μg/mL*hr, respectively.

Example 10 60% Solid Dispersion Using HPMCAS

A solid dispersion was prepared containing 60 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand HPMCAS Grade M using a Buchi B-290 mini spray drier. The soliddispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5%spray solution concentration, an inlet temperature of 80° C. at a flowrate of 35 mL/minute, drying gas flow rate of 40 m³/hour, nozzlepressure of 80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mmnozzle type. Secondary drying of the dispersion was done at 40° C. undervacuum for about 16 hours. The spray drying yielded 113.3 mg (67.2%yield) of the solid dispersion. The XRPD scan is shown in FIG. 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The solid dispersion was suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The results are in FIG. 12. The Cmax andAUC for the total drug species (colloidal+free) was 26.45 μg/mL and96.21 μg/mL*hr, respectively. The Cmax and AUC for the free drug specieswas 10.96 μg/mL and 42.83 μg/mL*hr, respectively.

Example 11 50% Solid Dispersion Using PVP-PA

A solid dispersion was prepared containing 50 weight percentN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand PVP-VA using a Buchi B-290 mini spray drier. The solid dispersionwas spray dried from a MeOH:THF (1:3) solvent system, a 3.9% spraysolution concentration, an inlet temperature of 100° C. at a flow rateof 30 mL/minute, drying gas flow rate of 40 m³/hour, nozzle pressure of80 psig, nozzle gas flow of 0.66 m³/hour, and a 1.5 mm nozzle type.Secondary drying of the dispersion was done at 50° C. under vacuum forabout 72 hours. The spray drying yielded 28.7 g (72.7% yield) of thesolid dispersion.

Example 12N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineFreebase Hemi-Ethanolate

Step 1: (E)-N′-(2-Cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide was coupled with4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropylacetate:acetic acid (65:35 v/v) at 45° C. to yield1-(4((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (91%).

Step 2: 1-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea wasagitated in tetrahydrofuran under basic conditions (2.5N NaOH), followedby the addition of p-toluenesulfonyl chloride. Water was charged toyieldN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(96%) as a mixture of polymorphs (generally a mixture containing one ormore of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P).

Step 3:N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminefrom Step 2 was triturated in ethanol at greater than 65° C. to provideN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol (89%).

The crystalline hemi-ethanolate (Form B Ethanol) XRPD scans are shown inFIGS. 1 and 7.

Dissolution testing was performed at a pH of 6.5 in phosphate buffer.The crystals (particles) were suspended in H₂O and added directly to thebuffer solution at 37° C. The dissolution profile was collected over aperiod of about 240 minutes. The Cmax and AUC for the free drug specieswas 0.44 μg/mL and 5.49 μg/mL*hr, respectively.

Example 13 Pharmaceutical Composition 1

Tablets containing the solid dispersions of any of Examples 1 to 11 maybe prepared in a conventional manner comprising:

Function Ingredient % of Blend API Solid dispersion 50 as prepared inExample 11 Disintegrant Crospovidone - 6 Polyplasdone ® Osmogen NaCl 5Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium0.25 Stearate Extragranular Binder/Diluent Microcrystalline 19.25cellulose - Avicel ® Osmogen NaCl 4.625 Osmogen KCl 4.625 DisintegrantPolyplasdone 4 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium0.25 Stearate

In one preparation, tablets were made using OPADRY II 85F92727 at 3% byweight as a tablet coating. The tablets contained 150 mg of API.

Example 14 Pharmaceutical Composition 2

Tablets containing the solid dispersions of any of Examples 1 to 11 maybe prepared in a conventional manner comprising:

Function Ingredient % of Blend API Solid dispersion 50 as prepared inExample 11 Disintegrant Crospovidone - 6 Polyplasdone ® DisintegrantNaHCO₃ 3 Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal Silicon 0.5Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Binder/DiluentMicrocrystalline 16.25 cellulose - Avicel ® Osmogen NaCl 4.625 OsmogenKCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal Silicon 0.5Dioxide Lubricant Magnesium 0.25 Stearate

In one preparation, tablets were made using OPADRY II 85F92727 at 3% byweight as a tablet coating. The tablets contained 150 mg of API.

Example 15 Pharmaceutical Composition 3

Tablets containing the solid dispersions of any of Examples 1 to 11 maybe prepared in a conventional manner comprising:

Function Ingredient % of Blend API Solid dispersion 50 as prepared inExample 11 Disintegrant Crospovidone - 6 Polyplasdone ® Osmogen NaCl10.625 Osmogen KCl 10.625 Filler Lactose 21.25 Glidant Colloidal Silicon0.5 Dioxide Lubricant Magnesium 0.25 Stearate Extragranular GlidantColloidal Silicon 0.5 Dioxide Lubricant Magnesium 0.25 Stearate

In one preparation, tablets were made using OPADRY II 85F92727 at 3% byweight as a tablet coating. The tablets contained 150 mg of API.

Example 16 Referential Pharmaceutical Composition—Powder-in-Capsule

A PIC composition was prepared containing 25 mg or 100 mg ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineas prepared in Example 12. The PIC composition was prepared in size 00white opaque hard gelatin capsules.

A dissolution test comparison was performed comparing the crystallinehemi-ethanolate PIC composition of Example 16 and the 50% PVP-VA soliddispersion (Example 11) tablet of Example 13 in 900 mL of 10 mM citratebuffer at 37° C. and a pH of 4.5, using USP Apparatus II at 75 rpm. Theresults are shown in FIG. 13.

Example 17 Stability Screen

A stability screen of the spray dried dispersions was completed at 40°C., 75% relative humidity under open conditions, in glass vials, over aperiod of 8 days. Results are shown in TABLE 2.

TABLE 2 HPLC Area % Time Example 1 Example 2 Example 3 Example 4Standard 99.39 99.39 99.39 99.39 As received 99.45 98.63 97.30 95.45 4days 99.21 96.10 93.03 90.89 8 days 99.35 93.16 86.63 87.15

The main degradant observed was the carbamate impurity, likely due tothe acidic nature of some of these polymers. XRPD analysis over thecourse of the study showed no evidence of crystallization for any soliddispersion of Examples 1-4.

Example 18 In Vivo Pharmacokinetics in Beagles

The solid dispersion of Example 1 was tested against a crystalline,micronized suspension formulation (d(v, 0.9)=3.0 μm) of Example 12 undernormal fasted conditions, as well as with pretreatment usingpentagastrin or famotidine. The solid dispersion of Example 1 wasprepared as a suspension in water and administered orally. Themicronized suspension of Example 12 was prepared as a suspension withSyrSpend® SF Dry reconstituted with water and administered orally. Toreduce variability, beagles were crossed over from pentagastrin tofamotidine after a 5 day washout period. Pentagastrin is a pH modifierto modify gastric pH to about 2 to 3, and famotidine is a pH modifier tomodify gastric pH to about 5 to 7.5 (Zhou, Rong, et al. “pH-DependentDissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs:Development of a Canine Model.” Pharm. Res. Vol. 22, No. 2 (February2005): pp. 188-192). There were four beagles per group. Group A receivedpentagastrin pretreatment, the micronized suspension of Example 12,followed by a 5 day washout period, then famotidine pretreatment, andfinally the micronized suspension of Example 12. Group B receivedpentagastrin pretreatment, the solid dispersion of Example 1, followedby a 5 day washout period, then famotidine pretreatment, and finally thesolid dispersion of Example 1. Group C received the micronizedsuspension of Example 12, followed by a 5 day washout period, andfinally the solid dispersion of Example 1. Results are shown in TABLE 3.

TABLE 3 AUC_(inf) Pretreatment Dosing Formulation (μg*hr/mL) C_(max)(μg/mL) None Micronized Suspension 7.43 ± 1.77 1.88 ± 0.35 of Example 12Solid Dispersion of 10.0 ± 2.7  2.29 ± 0.54 Example 1 6 μg/kg MicronizedSuspension 17.2 ± 2.7  3.29 ± 0.13 Pentagastrin of Example 12 SolidDispersion of 13.0 ± 3.6  3.12 ± 0.62 Example 1 40 mg/kg MicronizedSuspension 1.74 ± 0.39 0.514 ± 0.092 Famotidine of Example 12 SolidDispersion of 6.32 ± 2.88 1.45 ± 0.54 Example 1

It will be understood that the enumerated embodiments are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

What is claimed:
 1. A solid dispersion comprisingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a dispersion polymer, wherein the dispersion polymer is amethacrylate copolymer or a cellulosic polymer or cellulosic copolymer.2. The dispersion of claim 1, wherein theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis amorphous.
 3. The dispersion of claim 1, wherein theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis present in an amount of from about 0.1% to about 60% by weightrelative to the dispersion polymer.
 4. The dispersion of claim 1,wherein the dispersion polymer is Eudragit L100.
 5. The dispersion ofclaim 1, wherein the dispersion polymer is neutral or basic.
 6. Thedispersion of claim 1, wherein at least 95% theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis in amorphous form.
 7. A pharmaceutical composition comprising thesolid dispersion of claim 1 and one or more pharmaceutically acceptableexcipients.
 8. The pharmaceutical composition of claim 7, wherein adisintegrant is a pharmaceutically acceptable excipient of thecomposition.
 9. The pharmaceutical composition of claim 7, wherein thesolid dispersion ranges from about 25% to about 60% by weight.
 10. Thepharmaceutical composition of claim 8, wherein the disintegrant rangesfrom about 0.1 to about 20 weight %.
 11. The pharmaceutical compositionof claim 8, wherein the disintegrant is Crospovidone.
 12. Thepharmaceutical composition of claim 8, wherein the disintegrant issodium bicarbonate.
 13. The pharmaceutical composition of claim 8,wherein the disintegrant is Polyplasdone.
 14. A method for the treatmentof ErbB2 positive non-small cell lung (NSCLC) cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutical composition of claim
 7. 15. The method ofclaim 14, wherein the pharmaceutical composition is administered orally.16. The method of claim 14, wherein the pharmaceutical composition isadministered in the form of a tablet.
 17. A method of treating orpreventing a disease or disorder modulated by ErbB2, comprisingadministering to a subject in need of such treatment an effective amountof the pharmaceutical composition of claim 7.